The overall and specific goal of this application is the identification of novel high affinity and selective functional antagonists of the neuropeptide Y Y2 receptor subtype. We aim to identify, design and synthesize novel, potent, and selective Y2R antagonists as tools for research on alcohol dependence with potential as clinically effective therapeutic agents. We aim to achieve this goal via medicinal chemistry design based on existing Y2R ligands that are available or have been obtained in our high throughput screening efforts. The disease target, alcohol addiction and dependence, represents an enormous health burden on society and for which currently available pharmacotherapies have insufficient efficacy. We propose Y2R antagonism as a mechanism to achieve the therapeutic objective. While no clinical validation exists for the mechanism, the hypothesis supported by preclinical data from multiple sources. A translational research team composed of medicinal chemists, computational chemists, cell biologists, pharmacologists, and physiologists with extensive drug discovery experience is prepared to execute a molecule development program centered on the design, synthesis and evaluation of agents for that can be used in alcohol dependence research based on their actions at the NPY Y2 receptor. Compounds will be developed in an iterative cycle of ligand evaluation and re-design. Medicinal chemistry efforts will focus on development of new and better compounds. The in vitro pharmacology of novel compounds will be assessed in multiple cell-based assays and will include NPY receptor counterscreens to routinely determine potency and selectivity at a very early stage. DMPK properties of leads will be determined both in vitro and in vivo throughout the process as well. Additional in vivo assessments of compound activity on alcohol dependence, including a validated test for efficacy assessment in reducing alcohol self-administration in rats, will be performed in the NIH/NIAAA laboratory of Dr. Markus Heilig. All other work will be performed at extramural sites. Unique aspects of our approach include an early reliance upon selectivity data, DMPK information, and early animal efficacy studies.